Although diabetes mellitus is associated with the development of more atherosclerosis, the reasons for this are not entirely understood. Efforts during the past decade to develop animal models of diabetic macrovascular disease were confounded by the development of hyperlipidemia in many diabetic mice or the failure of hyperglycemia alone to accelerate atherosclerosis. We hypothesized that mice were deficient in a gene required to allow the toxic effects of hyperglycemia on arteries. Mice are relatively deficient in aldose reductase (AR), the enzyme that converts glucose to sorbitol. We discovered that LDL receptor knockout mice (Ldlr-/-) made diabetic with streptozotocin (STZ) treatment have accelerated, atherosclerosis when a transgene expressing human AR (hAR) is present. Moreover, heterozygous Ldlr-/- mice also have greater lesion size with STZ-treatment. This grant proposes to study the relationship between AR expression and murine atherosclerosis. The specfic aims are as follows: Aim 1. To determine the effects of hAR expression on macrovascular disease in diabetic models. Dietary and genetic models of insulin deficiency and insulin resistance will be crossed onto the Ldlr-/- background with and without hAR expression. Aim 2. To assess whether AR over-expression in endothelial cells or macrophages mediates hyperglycemia-induced atherosclerosis. These experiments will employ transplantion of bone marrow and production of new lines of transgenic AR expressing mice. Aim 3. To determine whether AR expression in endothelial cells and/or macrophages affects inflammatory processes in the setting of hyperglycemia. Tissue culture experiments will explore pathways relating hAR expression to inflammation and cellular cholesterol uptake. This information will then be used to study AR effects in vivo. These studies will, we expect, illustrate a genetic intervention that leads to reproducible diabetes-mediated acceleration of atherosclerosis in mice. This is significant because it will provide for a model to study this complication and suggest a therapeutic target for prevention of diabetic macrovascular disease.